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Dendritic arborization is critical for the establishment and maintenance of precise neural circuits. Vascular endothelial growth factor D (VEGF-D), well-characterized as a “lymphangiogenic” growth factor, reportedly maintains dendritic arborization and synaptic strength in the hippocampus of adult mice through VEGF receptor (VEGFR-3) signaling. Here, we investigated the effect of chronic VEGFR-3-specific activation on adipose arbor morphometry using the Adipo-VD mouse, a model of inducible, adipose-specific VEGF-D overexpression. We examined whether adipose tissue innervation was preserved or functionally different in Adipo-VD mice during stress in vivo and if VEGFR-3 signaling afforded neuroprotection to challenged neurons in vitro. Chronic VEGFR-3 signaling in Adipo-VD subcutaneous adipose tissue resulted in a reduction in the dendrite length, dendritic terminal branches (filament length), dendritic terminal branch volume (filament volume), but increased dendrite branching. We also identified reduced stimulus-evoked excitatory sympathetic nerve activity in Adipo-VD mice. Following 6-hydroxydopamine (6-OHDA) denervation, Adipo-VD dendritic arbors were preserved, including improved dendritic branch volume, length, and dendritic branches than in wildtype tissues. In vitro, we found that chronic elevation of VEGFR-3 signaling in developing mVC neurons changes the dendritic arbor complexity and improves stress-induced structure remodeling. Developing neurons are conferred neuroprotection against stress, potentially by upregulation of proteolytic conversion of pro-BDNF to mature BDNF. Mature neurons, however, display improved dendritic arbor complexity, and unaltered dendritic structural remodeling and improved resistance to stress with VEGFR-3 signaling. Overall, chronically increasing VEGFR-3 signaling in neurons has a synergistic impact on neurosensitization and neuroprotection during stress.
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AIM: Fluid and macromolecule transport from the interstitium into and through lymphatic vessels is necessary for tissue homeostasis. While lymphatic capillary structure suggests that passive, paracellular transport would be the predominant route of macromolecule entry, active caveolae-mediated transcellular transport has been identified in lymphatic endothelial cells (LECs) in vitro. Caveolae also mediate a wide array of endothelial cell processes, including nitric oxide regulation. Thus, how does the lack of caveolae impact "lymphatic function"? METHODS: Various aspects of lymphatic transport were measured in mice constitutively lacking caveolin-1 ("CavKO"), the protein required for caveolae formation in endothelial cells, and in mice with a LEC-specific Cav1 gene deletion (Lyve1-Cre x Cav1flox/flox ; "LyCav") and ex vivo in their vessels and cells. RESULTS: In each model, lymphatic architecture was largely unchanged. The lymphatic conductance, or initial tissue uptake, was significantly higher in both CavKO mice and LyCav mice by quantitative microlymphangiography and the permeability to 70 kDa dextran was significantly increased in monolayers of LECs isolated from CavKO mice. Conversely, transport within the lymphatic system to the sentinel node was significantly reduced in anaesthetized CavKO and LyCav mice. Isolated, cannulated collecting vessel studies identified significantly reduced phasic contractility when lymphatic endothelium lacks caveolae. Inhibition of nitric oxide synthase was able to partially restore ex vivo vessel contractility. CONCLUSION: Macromolecule transport across lymphatics is increased with loss of caveolae, yet phasic contractility reduced, resulting in reduced overall lymphatic transport function. These studies identify lymphatic caveolar biology as a key regulator of active lymphatic transport functions.
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